This area of investigation began with the demonstration of monoclonal anti-MAG antibodies in patients with mixed sensory-motor polyneuropathies occurring in association with IgM gammopathy (paraproteinemia). It was subsequently demonstrated that these anti-MAG antibodies were all directed toward carbohydrate epitopes in MAG and cross-reacted with 19 to 28 kD glycoproteins of PNS myelin and a sphingoglycolipid, sulfate-3- glucuronyl paragloboside (SGPG). Monoclonal antibodies that are MAG/SGPG-negative in patients with IgM gammopathy and neuropathy frequently react with ganglioside antigens in nerve. Previous results from our laboratory and others had shown a strong correlation of high titer, monoclonal and polyclonal antibodies to G-M1-ganglioside with motor neuropathies, In the current year, we completed studies on a patient with a predominantly sensory neuropathy and a monoclonal IgM antibody that binds strongly to G-D1b-ganglioside and some other minor gangliosides that also contain a disialosyl group. Interestingly, two other patients with sensory neuropathy and antibodies of similar specificity have been reported, suggesting that antibodies of this general specificity may play a role in the pathogenesis of sensory neuropathies. In addition, we identified other neuropathy patients with monoclonal anti-glycolipid antibodies, including one with monoclonal IgA reacting with the major LM1 ganglioside of peripheral nerve myelin. Little is known about the molecular mechanisms by which antibodies to acidic glycolipids in patients with demyelinating neuropathy exert their pathogenic effects. In order to probe the function of acidic glycolipids in myelination and to understand mechanisms by which the human anti- glycolipid antibodies may perturb function, we have begun an investigation of gangliosides in differentiating Schwann cells. In comparison to Schwann cells cultured in the absence of neurons in serum- containing medium on polylysine, culturing the Schwann cells on a basement membrane substratum (Matrigel) resulted in increased incorporation of radioactive galactose into gangliosides (predominantly GM3) and had no effect on incorporation into the galactosphingoglycolipids characteristic of myelin. Thus, although basement membrane is well known to be required for myelination, its presence in the absence of neurons drives Schwann cell lipid metabolism toward gangliosides rather than toward the galactosphingolipids enriched in myelin.